PROJECT SUMMARY/ABSTRACT The placenta serves multifaceted roles during pregnancy by ensuring proper growth and development of the fetus. Acting as a critical interface between the fetal and maternal blood circulations, the placenta actively exchanges nutrients and waste. The placenta also acts as a protective barrier by restricting the transfer of some xenobiotics into the fetal compartment. This placental barrier is enabled by the enrichment of efflux pumps on the maternal-facing membrane of placental cells called syncytiotrophoblasts. Efflux pumps, such as the breast cancer resistance protein (BCRP/ABCG2), selectively transport xenobiotics away from the placenta and back into maternal circulation, in effect protecting the fetus from adverse exposures. Impairment of BCRP function during pregnancy may lead to greater accumulation of chemicals in the placental and fetal compartments and potentially result in deleterious effects. Our laboratory recently discovered that BCRP can transport zearalenone (ZEA), a mycotoxin produced by the Fusarium fungus. ZEA is a nonsteroidal estrogen agonist that contaminates various cereal crops including maize, wheat, rice, and sorghum. Increasing temperatures across the globe are favoring the growth of fungi in the food supply as well as their production of mycotoxins making it critical to understand the human health effects of ZEA. Data in rodents and livestock have demonstrated that ZEA is a reproductive and developmental toxin, however, its effects on human health are less clear particularly in response to in utero exposures. The research aims in this fellowship application will characterize the placental disposition and endocrine activity of ZEA. Aim 1 will determine the effect of ZEA exposure on placental functions using ex vivo placental explants obtained from term, healthy pregnant women. Aim 2 will characterize the disposition of ZEA in placentas and fetuses from Bcrp-/- mice. The expected outcomes are that 1) ZEA will induce the production of hormones and activate markers of syncytialization, 2) ZEA-mediated up-regulation of hormones and syncytialization markers will occur at lower concentrations when BCRP is inhibited, and 3) Bcrp- null fetuses and placentas will have higher concentrations of ZEA and perturbed placental mRNA profiles when compared to wild-type counterparts. Taken together, this research will examine the protective role of the BCRP efflux transporter and the adverse effects of ZEA on fetal and placental development. These data are significant because BCRP protein expression in the placenta varies up to 14-fold among women. As a result, babies with low placental BCRP expression may be at greater risk of ZEA exposure. The proposed research will be completed as part of a Ph.D. thesis. The described coursework, training, and laboratory activities will greatly enhance the PI?s development into an independent scientist in the field of toxicology.